Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA) are the most common monosymptomatic inherited optic neuropathies that generally lead to optic nerve degeneration and visual failure.
LHON is a mitochondrial genetic disease characterized by bilateral loss of central vision owing to focal degeneration of the optic nerve. It was first described by Dr. Theodor Leber who reported the characteristic pattern of visual loss in 1871. It was not until 1972 that Dr. Robert Erickson proposed the non-Mendelian pattern of inheritance and suggested a mitochondrial DNA (mtDNA) mutation. The first association with the particular mutation m.11778G>A was not identified until 1988 by Dr. Douglas Wallace. It is now known that over 95% of LHON pedigrees harbor one of three mitochondrial DNA (mtDNA) point mutations m.3460G>A, m.11778G>A and m.14484T>C which all involve genes encoding complex I of the mitochondrial respiratory chain.
The onset of visual loss ranges from age 8 to 60 but occurs mostly between the age of 15 and 30 years. However, visual deterioration can already occur during the first seven years of life. The disease predominantly affects males.
Generally, LHON carriers remain asymptomatic until they experience blurring or clouding of vision in one eye, the second eye becoming affected sequentially with a delay of about six to eight weeks. LHON patients experience a rapid and painless loss of central vision accompanied by the fading of colors especially in the green/red field. Visual acuity usually reaches levels of 20/400 in a few months. At fundus examination the characteristic signs include vascular tortuosity of the central retinal vessels, circumpapillary telangiectatic microangiopathy, swelling of the retinal nerve fiber layer around the disc and lack of leakage on fluorescein angiography. After 6 months optic atrophy is a universal feature. Although visual recovery has been observed in rare cases, the chances of improvement are the least in patients with a point mutation m.11778G>A. LHON is a devastating disorder with the majority of the patients showing no functional improvement and becoming legally blind.
Dominant Optic Atrophy (DOA) also known as autosomal dominant optic atrophy, Kjer type; Kjer optic atrophy; or Kjer's autosomal dominant optic atrophy, is characterized by a slow progressive bilateral loss of central vision starting in childhood and progressing in adult life. It was first described in 1886 by D. Batten. It is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers.
Although the visual prognosis is better than compared to LHON, DOA results in significant visual impairment with about half of all affected individuals failing the driving standards, and 13-46% being registered as legally blind. The predominant color defect in DOA is dyschromatopsia involving both the blue-yellow and the red-green axes. Patients with DOA experience diffuse atrophy of the retinal ganglion cell layer, loss of myelin and fibrillary gliosis along the anterior visual pathways extending to the lateral geniculate body.
Vision loss in DOA is due to optic nerve fiber loss from mitochondrial dysfunction. Dominant optic atrophy is associated with mutation of the OPA1 gene. Six other chromosomal genes are described as causing optic atrophy: OPA2 (obscure), OPA3 (dominant), OPA4 (dominant), OPA5 (dominant), OPA6 (recessive) and OPA7 (dominant). Dominant optic atrophy demonstrates genetic heterogeneity, which is where a single disease can be caused by various genetic defects at different loci. Over 60 different mutations of the OPA1 gene causing DOA have been reported.
There is thus a critical and unmet need for effective treatments for Leber's hereditary optic neuropathy and dominant optic atrophy.